RUI: Probing the Mechanotransduction of Disturbed Flow in Brain Vasculature

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Aneurysms in blood vessels of the head pose a substantial health risk to the general population. The vast majority of brain aneurysms form at branch points and junctions of arteries, where blood flow is 'disturbed' by sudden changes in its flow path. Disturbed blood flow alters the mechanical force exerted on cells lining cerebral arteries, though the contribution of these forces to aneurysm formation is not fully known. Determining the effect of flow-induced forces on cells inside a living brain is difficult, necessitating the development of model vascular systems that reproduce what happens in life. This model must mimic the unique the 'blood-brain barrier' that changes how the brain vasculature works compared to vessels in the rest of the body. The research will use such a model to determine the effect of disturbed flow on cellular processes associated with aneurysm formation. The project will yield a better understanding of the effects of disturbed blood flow in the brain, and suggest molecular targets that may prevent aneurysm formation in at-risk patients. The research will train undergraduates and graduate students to perform laboratory work. High school students from Camden, NJ will be recruited to work in the laboratory. The grant will add to Rowan University's effort to build a research program in southern New Jersey. The overall goal of this project is to determine the biological response of cerebral endothelial cells to disturbed fluid flow and to investigate the molecular mechanisms underlying this response. The spatial correlation between saccular aneurysms and arterial bifurcations is striking, lending credence to the accepted view that disturbed flow at the sites of bifurcation contributes to the formation and progression of aneurysms. These studies rely on a three-dimensional, in vitro model of a cerebral artery bifurcation. Microparticle image velocimetry is used in combination with computational fluid dynamics to characterize the shear stress profiles exerted on the endothelium within this model. Gene and protein expression of matrix remodeling markers by endothelial cells will be measured in response to the applied fluid flow regimes. Studies will test the hypothesis that cd44 and its downstream effectors function as a mechanosensor of disturbed flow in cerebral vasculature. The central hypothesis is that disturbed flow-mediated activation of CD44 results in tight junction disruption and matrix metalloproteinase activation through RhoA GTPase. Identification of the mechanism responsible for transducing disturbed flow not only advances the fundamental understanding of how cells respond to mechanical forces, but also clarifies why intracranial aneurysms form in proximity to arterial bifurcations.